Method of reducing the undesirable gastrointestinal effects of prostaglandin synthetase inhibitors

ABSTRACT

There is disclosed concomitant systemic administration of prostaglandins of the PGB-type, for example, PGB2, and a prostaglandin synthetase inhibitor, for example, indomethacin, aspirin, or phenylbutazone, to mammals, including humans. Thereby the undesirable gastrointestinal effects of the synthetase inhibitor are reduced.

United States Patent 1 n 1 Robert 1 Oct. 7, 1975 METHOD OF REDUCING THE [56] References Cited UNDESIRABLE GASTROINTESTINAL UNITED STATES PATENTS EFFECTS OF PROSTAGLANDIN 3,781,429 12/1973 Partridge et al. 424/273 SYNTHETASE INHIBITORS Inventor: Andre Robert, Kalamazoo Township, Kalamazoo County, Mich.

Assignee: The Upjohn Company, Kalamazoo,

Mich.

Filed: Jan. 28, 1974 Appl. No.: 437,446

Int.Cl. ..A61K3l/l9;A61K31/6l; A61K3l/215;A6lK3l/415 Field of Search 424/305, 318, 273, 234,

Primary Examiner-Sam Rosen Attorney, Agent, or Firm-Earl C. Spaeth; Bruce Stein 5 7 ABSTRACT 14 Claims, No Drawings METHOD OF REDUCING THE UNDESIRABLE GASTROINTESTINAL EFFECTS OF PROSTAGLANDIN SYNTHETASE INHIBITORS This invention relates to an improvement in a known process of administration of certain medicinal agents to mammals, including humans, to accomplish a desired medicinal result. In particular, this invention relates to an improvement in the process of systemic administration of a prostaglandin synthetase inhibitor to a mammal, said improvement comprising concomitant systemic administration of an amount of a prostaglandin of the PGB-type effective to reduce the undesirable gastrointestinal effects of said prostaglandin synthetase inhibitor.

According to Takeguchi et al., Prostaglandins, 2, 169 (1972), Prostaglandin synthetase is a microsomal enzyme complex, which catalyzes the oxidative cyclization of unsaturated C fatty acids, such as arachidonic acid, into prostaglandins (PG) in the presence ofa suitable coenzyme. See also Nugteren et al., Rec. Trav. Chim. Pays-Bas. 85, 405 (1966); Hamberg et al., J. Biol. Chem. 242, 5336 (1967), and Sih et al., J. Am. Chem. Soc. 92, 6670 1970). This oxidative cyclization is presently thought to be an in vivo physiological process initiated by one or more physiological mechanisms of as yet unknown nature.

1n the case of arachidonic acid (I), this oxidative cyclization is formulated as follows, leading to the prostaglandins known as PGE (II) and/or PGF (III) prostaglandin synthetase It is readily determined in vitro whether or not a particular substance is a prostaglandin synthetase inhibitor. See, for example, Takeguchi et al., above cited.

Many of the substances now known to be prostaglandin synthetase inhibitors are also members of a class known descriptively as non-steroidal anti-inflammatory agents. See, for example, Vane, Nature New Biology, 231, 232 (1971 Takeguchi et al., above cited, and references cited in Takeguchi et al. Included within this class of substances are the well-known antiinflammatory agents indomethacin, aspirin, and phenylbutazone. Others are rnefenamic acid, flufenamic acid, naproxen, 2-phenoxyphenylpropionic acid, (+)3-chloro-4-cyclohexyl-a-methylphenylacetic acid, and ibuprofen.

It is readily determined in vivo whether or not particular substances, including substances known to be prostaglandin synthetase inhibitors, are antiinflammatory agents. See, for example, R. A. Turner, Screening Methods in Pharmacology", Academic Press, New York, Chapter 13, pp. 152-163 (1965), and especially, Winder et al., J. Pharmacol. Exp. Ther. 141, 369 (1963).

It is now well known that administration of certain non-steroidal anti-inflammatory agents, especially by the oral or rectal route, to humans for antiinflammatory purposes often causes undesirable gastrointestinal effects including but not limited to abdominal pain, single or multiple ulcerations, nodules, adhesions, and other types of lesions, bleeding, anorexia, nausea, and the like. See, for example, Boardman et al., Ann. rheum. Dis. 26, 127 (1967); Taylor et al., Brit. Med. J. 4, 734 1968); Fischer et al., Am. J. Gastroent. 51, 42 1969); Sturges et al., Am. J. Gastroent. 59, 162 (1973), Chapman et al., Out, 10, 443 (1909); Smith, Ann. NY. Acad. Sci. 86, 38 (1960); and Gault et al., Ann. Int. Med. 68, 906 (1968). Discontinuing administration of the anti-inflammatory agent usually results in alleviation and later substantially complete relief from these undesirable gastrointestinal effects, especially healing of the ulcers. But meanwhile, the patient has no relief from the inflammatory disease for which he was being treated.

it has been reported that the ulcerogenic effect induced by certain non-steroidal anti-inflammatory agents in rats is inhibited by concomitant oral administration of certain prostaglandins of the E and A series, including PGE PGE PGE l3,l4-dihydro-PGE,, and the corresponding 1 l-deoxy-PGE and PGA compounds. See Partridge et al., US. Pat. No. 3,781,429.

I have now made the surprising discovery that prostaglandins of the PGB-type are useful in reducing the undesirable gastrointestinal effects resulting from systemic administration of anti-inflammatory prostaglandin synthetase inhibitors, and are used for that purpose by concomitant administration of the PGBtype prostaglandin and the anti-inflammatory prostaglandin syn thetase inhibitor. This novel process improvement is useful, for example, in reducing the undesirable gastrointestinal effects resulting from systemic administration of indomethacin, phenylbutazone, and aspirin. These are substances specifically mentioned in Partridge et al. as non-steroidal antiinflammatory agents. But these are also known to be prostaglandin synthetase inhibitors. The novel process improvement of this invention is useful only in reducing undesirable gastrointestinal effects caused by antiflammatory agents which are also prostaglandin synthetase inhibitors. Undesirable gastrointestinal effects caused by antiflammatory agents which are not prostaglandin synthetase inhibitors are not expected to be reduced by concomitant administration of a PGB-type prostaglandin.

Prostaglandins may be considered as derivatives of a parent substance known as prostanoic acid, having the following formula and atom numbering:

x 6 4 2 COOH I 7\/E\/3\/ 1 Q 14 1a 1 1e 1 20 The prostaglandin known as PGB, has the formula:

COOH Prostaglandin E: (PGB has the formula:

Prostaglandin B (PGB has the formula:

VII

13, l 4-Dihydroprostaglandin B, 13, l 4'dihydro-PGB has the formula VIII Thus, it can be seen that PGB-type prostaglandins all have the structural feature:

with a carboxyl-terminated carbon chain attached at carbon atom (a) and a carbon chain attached at carbon atom (b), with an alpha (S) hydroxy on the 3rd carbon atom of the latter chain. For the purposes of this invention, a PGB-type prostaglandin is defined as any compound, optically active or racemic, with the structural features above defined and also with 4 to 9 carbon atoms in a chain between the carboxylate function and the ring at (a) and with 4 to 12 carbon atoms in a chain attached to the ring at (b). The ring and either chain may have substituents, hetero atoms, and/or carboncarbon double (cis or trans) or triple bonds.

P68 P63 P68 13, l 4-dihydro PGB,, and numerous salts and esters of those are known in the art. Moreover, numerous analogs of PGB PGB P68 and l3,14-dihydro-PGB,, and salts and ester of those, are known in the art. See, for example, Pharmacol. Rev. 20, l 1968) and references cited therein. See also U.S. Pat. Nos. 3,069,322; 3,598,858; 3,767,701; 3,767,700; 3,767,697; 3,767,698; 3,759,978; and 3,775,462. See

also German Offenlegungschrift Nos. 2,210,697; 2,036,471; 2,0] 1,969; 2,209,990; 2,154,309; 2,164,184; 2,217,044; 2,221,443; 2,320,368;

2,320,552; 2,322,673; and 2,317,019.

Any of the known PGB-type free acids, salts, and esters as exemplified in the above-cited publications are useful in the novel process improvement of this invention. Moreover, any PGB-type free acid, salt, or ester which is not toxic at the effective dose and which has the structural features defined above is also useful in the novel process improvement of this invention.

The administration to animals and especially to humans of an anti-inflammatory synthetase inhibitor for treatment of inflammation and related physiological condition is not by itself part of this invention. Rather, as discussed above, this invention is an improvement in the administration of anti-inflammatory synthetase inhibitors to mammals and especially to humans.

In order to practice this novel improvement, the antiinflammatory synthetase inhibitor, for example, indo methacin, aspirin, or phenylbutazone is administered in any of the ways known in the art, to alleviate an inflammatory condition, for example, in any dosage regimen and by any of the known routes of systemic administration. It is known, however, that undesirable gastrointes tinal efiects most often result when the route of administration of the anti-inflammatory substance is oral or rectal, and when relatively large amounts of the substance are administered over a prolonged period of time. It is for such routes of administration and for such dosage regimens that the novel improvement which is this invention is most useful.

The prostaglandin of the PGB-type is administered along with the anti'inflammatory prostaglandin synthetase inhibitor either by the same route of administration or by a different route. For example, if the antiinflammatory substance is being administered orally, the PGB-type prostaglandin is also administered orally or, alternatively, is administered rectally in the form of a suppository or, in the case of women, vaginally in the form of a suppository or a vaginal device for slow release, for example, as described in U.S. Pat. No. 3,545,439. Alternatively, if the anti-inflammatory substance is being administered rectally, the PGB-type prostaglandin is also administered rectally or, alternatively, orally or, in the case of women, vaginally. It is especially convenient when the administration route is to be the same for both anti-inflammatory substance and PGB-type prostaglandin, to combine both into a single dosage form.

Dosage forms for both the anti-inflammatory substance and the PGB-type prostaglandin are prepared by methods known in the art. See, for example, Partridge et al., above cited.

Among the PGB'type prostaglandins to be used according to this invention, P013, and P68, are especially preferred. Also especially preferred are PGB, and PGB analogs wherein the molecular structure is the same as in PGB or PGB i.e., formulas V and VI,

above, except that there are one or 2 methyl or ethyl groups at C-l6 rather than hydrogens. These are known analogs of PG and PGB See, for example, German Offenlegungschrift Nos. 2,210,697 and 2,217,044.

Also preferred among the PGB-type prostaglandins to be used according to this invention are the free acid form, the salt form wherein the cation is pharmaceutically acceptable, and the ester fonn wherein the alcohol portion is alkyl, especially alkyl of one to 4 carbon atoms, inclusive, more especially methyl or ethyl.

The dosage regimen for the PGB-type prostaglandin in accord with this invention will depend upon a variety of factors, including the type, age, weight, sex, and medical condition of the mammal, the nature and dosage regimen of the anti-inflammatory synthetase inhibitor being administered to the mammal, the sensitivity of the particular individual mammal to the particular synthetase inhibitor with regard to gastrointestinal effeels, and the particular PGB-type prostaglandin to be administered. For example, not every human in need of an anti-inflammatory substance experiences the same adverse gastrointestinal effects when taking the substance. The gastrointestinal effects will frequently vary substantially in kind and degree. But it is within the skill of the attending physician or veterinarian to determine that administration of the anti-inflammatory substance is causing undesirable gastrointestinal effects in the human or animal subject, and to prescribe an effective amount of the PGB-type prostaglandin to reduce and then substantially to eliminate those undesirable effects. In doing that, the physician or veterinarian would, of course, start at a relatively low concomitant dose of the PGB-type prostaglandin, for example, about 0.025 mg./kg./day of PGB or about 0.l ug/kg/day of l6,l6-dimethyl-PGB and observe the response of the human or animal patient for a few days. The dose of the PGB-type prostaglandin is then adjusted downward or upward until the minimum effective dose is found. For example, in the case of P68 the maximum needed dose is usually about 25 mg./kg./day and in the case of 16,16-dimethyl-PGB the maximum needed dose is usually about pg/kg/day, although it may be necessary occasionally to exceed these doses when large amounts of the inflammatory substance are needed for a particular medical indication or when the gastrointestinal response of a particular subject to the anti-inflammatory substance is expecially severe and there is a sound medical reason for maintaining the subject on that particular antiinflammatory substance. Once the minimum effective dose of the particular PCB-type compound is determined for a particular subject, it is advantageous to provide the subject with a single dosage form which contains both the desired amount of the antiinflammatory substance and the amount of the PGB- type prostaglandin effective to obtain the desired gastrointestinal result.

Since not all animal and human subjects have adverse gastrointestinal responses to administration of an antiinflammatory prostaglandin synthetase inhibitor, rational medical therapy indicates that the PGB-type compound not be administered until the need for that appears in any particular animal or human subject. But when this need is observed, it can be expected that, at least in some subjects, a higher dose level of the P- type compound will be needed along with the antiinflammatory substance to allow the gastrointestinal tract to return to normal during continued administration of the anti-inflammatory substance than will later be necessary to maintain a normal gastrointestinal tract. It is, however, within the skill of the attending physician or veterinarian to adjust the dose of the P68- type substance to meet the needs of the individual human or animal subject especially in the usual situations involving long term regimens of antiinflammatory substances. In this respect, the term effective amount of the PGB-type substance will mean amounts effective at various time periods during administration of an anti-inflammatory substance. An amount of the PGB-type substance effective to allow healing of existing gastrointestinal ulcers, for example, will not necessarily be the same and, indeed, is likely to be more than the amount effective to avoid formation of future ulcers. The process improvement which is this invention includes both of these concepts of effective amount."

I claim:

1. In the process of systemic administration of an anti-inflammatory prostaglandin synthetase inhibitor to a mammal, the improvement which comprises concomitant systemic administration of an amount of a prostaglandin of the PGB-type effective to reduce the undesirable gastrointestinal effects of said prostaglandin synthetase inhibitor.

2. The process of claim 1 wherein the mammal is a human.

3. The process of claim 2 wherein the synthetase inhibitor is administered orally or rectally, and the prostaglandin is administered orally, rectally, or, in the case of a woman, vaginally.

4. The process of claim 2 wherein the synthetase inhibitor and the prostaglandin are both administered orally.

5. The process of claim 3 wherein the synthetase inhibitor is indomethacin, aspirin, or phenylbutazone.

6. The process of claim 4 wherein the synthetase inhibitor is indomethacin, aspirin, or phenylbutazone.

7. The process of claim 3 wherein the prostaglandin is of the PGB -type.

8. The process of claim 4 wherein the prostaglandin is of the PGB -type.

9. The process of claim 5 wherein the prostaglandin is of the PGB -type.

10. The process of claim 6 wherein the prostaglandin is of the PGB -type.

1 l. The process of claim 3 wherein the prostaglandin is PGB, or a pharrnaceutically acceptable salt thereof.

12. The process of claim 4 wherein the prostaglandin is P68 or a pharmaceutically acceptable salt thereof.

13. The process of claim 5 wherein the prostaglandin is PGB or a pharmaceutically acceptable salt thereof.

14. The process of claim 6 wherein the prostaglandin is PS8, or a pharmaceutically acceptable salt thereof. =l m 

1. IN THE PROCESS OF SYSTEMIC ADMINISTRATION OF AN ANTI-INFLAMMATORY PROSTAGLADIN SYNTHETASE INHIBITOR TO A MAMMAL THE IMPROVEMENT WHICH COMPRISES CONCOMITANT SYSTEMIC ADMINISTRATION OF AN AMOUNT OF A POROSTAGLADIN OF THE PGB-TYPE EFFECTIVE TO REDUCE THE UNDESIRABLE GASTROINTESTINAL EFFECTS OF SAID PROSTAGLADIN SYNTHETASE INHIBITOR.
 2. The process of claim 1 wherein the mammal is a human.
 3. The process of claim 2 wherein the synthetase inhibitor is administered orally or rectally, and the prostaglandin is administered orally, rectally, or, in the case of a woman, vaginally.
 4. The process of claim 2 wherein the synthetase inhibitor and the prostaglandin are both administered orally.
 5. The process of claim 3 wherein the synthetase inhibitor is indomethacin, aspirin, or phenylbutazone.
 6. The process of claim 4 wherein the synthetase inhibitor is indomethacin, aspirin, or phenylbutazone.
 7. The process of claim 3 wherein the prostaglandin is of the PGB2-type.
 8. The process of claim 4 wherein the prostaglandin is of the PGB2-type.
 9. The process of claim 5 wherein the prostaglandin is of the PGB2-type.
 10. The process of claim 6 wherein the prostaglandin is of the PGB2-type.
 11. The process of claim 3 wherein the prostaglandin is PGB2 or a pharmaceutically acceptable salt thereof.
 12. The process of claim 4 wherein the prostaglandin is PGB2 or a pharmaceutically acceptable salt thereof.
 13. The process of claim 5 wherein the prostaglandin is PGB2 or a pharmaceutically acceptable salt thereof.
 14. The process of claim 6 wherein the prostaglandin is PGB2 or a pharmaceutically acceptable salt thereof. 